text: A ubiquitous signaling motif that exhibits ultrasensitivity is the MAPK (mitogen-activated protein kinase) cascade, which can take a graded input signal and produce a switch-like output, such as gene transcription or cell cycle progression. In this common motif, MAPK is activated by an earlier kinase in the cascade, called MAPK kinase, or MAPKK. Similarly, MAPKK is activated by MAPKK kinase, or MAPKKK. These kinases are sequentially phosphorylated when MAPKKK is activated, usually via a signal received by a membrane-bound receptor protein. MAPKKK activates MAPKK, and MAPKK activates MAPK.  Ultrasensitivity arises in this system due to several features:
  # MAPK and MAPKK both require two separate phosphorylation events to be activated.
  # The reversal of MAPK phosphorylation by specific phosphatases requires an increasing concentration of activation signals from each prior kinase to achieve an output of the same magnitude.
  # The MAPKK is at a concentration above the K for its specific phosphatase and MAPK is at a concentration above the K for MAPKK.
  Besides the MAPK cascade, ultrasensitivity has also been reported in muscle glycolysis, in the phosphorylation of isocitrate dehydrogenase and in the activation of the calmodulin-dependent protein kinase II (CAMKII).
  An ultrasensitive switch has been engineered by combining a simple linear signaling protein (N-WASP) with one to five SH3 interaction modules that have autoinhibitory and cooperative properties.  Addition of a single SH3 module created a switch that was activated in a linear fashion by exogenous SH3-binding peptide.  Increasing number of domains increased ultrasensitivity.  A construct with three SH3 modules was activated with an apparent Hill coefficient of 2.7 and a construct with five SH3 module was activated with an apparent Hill coefficient of 3.9.